Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens

Two plasmid-encoded dihydrofolate reductase (DHFR) isoforms, DfrA1 and DfrA5, that give rise to high levels of resistance in Gram-negative bacteria were structurally and biochemically characterized to reveal the mechanism of TMP resistance and to support phylogenic groupings for drug development aga...

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Autores principales: Krucinska, Jolanta, Lombardo, Michael N., Erlandsen, Heidi, Estrada, Alexavier, Si, Debjani, Viswanathan, Kishore, Wright, Dennis L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106665/
https://www.ncbi.nlm.nih.gov/pubmed/35562546
http://dx.doi.org/10.1038/s42003-022-03384-y
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author Krucinska, Jolanta
Lombardo, Michael N.
Erlandsen, Heidi
Estrada, Alexavier
Si, Debjani
Viswanathan, Kishore
Wright, Dennis L.
author_facet Krucinska, Jolanta
Lombardo, Michael N.
Erlandsen, Heidi
Estrada, Alexavier
Si, Debjani
Viswanathan, Kishore
Wright, Dennis L.
author_sort Krucinska, Jolanta
collection PubMed
description Two plasmid-encoded dihydrofolate reductase (DHFR) isoforms, DfrA1 and DfrA5, that give rise to high levels of resistance in Gram-negative bacteria were structurally and biochemically characterized to reveal the mechanism of TMP resistance and to support phylogenic groupings for drug development against antibiotic resistant pathogens. Preliminary screening of novel antifolates revealed related chemotypes that showed high levels of inhibitory potency against Escherichia coli chromosomal DHFR (EcDHFR), DfrA1, and DfrA5. Kinetics and biophysical analysis, coupled with crystal structures of trimethoprim bound to EcDHFR, DfrA1 and DfrA5, and two propargyl-linked antifolates (PLA) complexed with EcDHFR, DfrA1 and DfrA5, were determined to define structural features of the substrate binding pocket and guide synthesis of pan-DHFR inhibitors.
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spelling pubmed-91066652022-05-15 Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens Krucinska, Jolanta Lombardo, Michael N. Erlandsen, Heidi Estrada, Alexavier Si, Debjani Viswanathan, Kishore Wright, Dennis L. Commun Biol Article Two plasmid-encoded dihydrofolate reductase (DHFR) isoforms, DfrA1 and DfrA5, that give rise to high levels of resistance in Gram-negative bacteria were structurally and biochemically characterized to reveal the mechanism of TMP resistance and to support phylogenic groupings for drug development against antibiotic resistant pathogens. Preliminary screening of novel antifolates revealed related chemotypes that showed high levels of inhibitory potency against Escherichia coli chromosomal DHFR (EcDHFR), DfrA1, and DfrA5. Kinetics and biophysical analysis, coupled with crystal structures of trimethoprim bound to EcDHFR, DfrA1 and DfrA5, and two propargyl-linked antifolates (PLA) complexed with EcDHFR, DfrA1 and DfrA5, were determined to define structural features of the substrate binding pocket and guide synthesis of pan-DHFR inhibitors. Nature Publishing Group UK 2022-05-13 /pmc/articles/PMC9106665/ /pubmed/35562546 http://dx.doi.org/10.1038/s42003-022-03384-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Krucinska, Jolanta
Lombardo, Michael N.
Erlandsen, Heidi
Estrada, Alexavier
Si, Debjani
Viswanathan, Kishore
Wright, Dennis L.
Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens
title Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens
title_full Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens
title_fullStr Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens
title_full_unstemmed Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens
title_short Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens
title_sort structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in gram-negative pathogens
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106665/
https://www.ncbi.nlm.nih.gov/pubmed/35562546
http://dx.doi.org/10.1038/s42003-022-03384-y
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